
#' Perform all Mendelian randomization tests
#'
#' @param dat Harmonised exposure and outcome data. Output from [harmonise_data()].
#' @param parameters Parameters to be used for various MR methods. Default is output from [default_parameters()].
#' @param method_list List of methods to use in analysis. See [mr_method_list()] for details.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{mr}{Table of MR results}
#' \item{extra}{Table of extra results}
#' }
mr <- function(dat, parameters=default_parameters(), method_list=subset(mr_method_list(), use_by_default)$obj)
{
	mr_tab <- plyr::ddply(dat, c("id.exposure", "id.outcome"), function(x1)
	{
		# message("Performing MR analysis of '", x1$id.exposure[1], "' on '", x18WII58$id.outcome[1], "'")
		x <- subset(x1, mr_keep)
		if(nrow(x) == 0)
		{
			message("No SNPs available for MR analysis of '", x1$id.exposure[1], "' on '", x1$id.outcome[1], "'")
			return(NULL)
		} else {
			message("Analysing '", x1$id.exposure[1], "' on '", x1$id.outcome[1], "'")
		}
		res <- lapply(method_list, function(meth)
		{
			get(meth)(x$beta.exposure, x$beta.outcome, x$se.exposure, x$se.outcome, parameters)
		})
		methl <- mr_method_list()
		mr_tab <- data.frame(
			outcome = x$outcome[1],
			exposure = x$exposure[1],
			method = methl$name[match(method_list, methl$obj)],
			nsnp = sapply(res, function(x) x$nsnp),
			b = sapply(res, function(x) x$b),
			se = sapply(res, function(x) x$se),
			pval = sapply(res, function(x) x$pval)
		)
		mr_tab <- subset(mr_tab, !(is.na(b) & is.na(se) & is.na(pval)))
		return(mr_tab)
	})

	return(mr_tab)
}


#' Get list of available MR methods
#' 
#' @export
#' @return character vector of method names
mr_method_list <- function()
{
	a <- list(
		list(
			obj="mr_wald_ratio",
			name="Wald ratio",
			PubmedID="",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=FALSE
		),
		# list(
		# 	obj="mr_meta_fixed_simple",
		# 	name="Fixed effects meta analysis (simple SE)",
		# 	PubmedID="",
		# 	Description="",
		# 	use_by_default=FALSE,
		# 	heterogeneity_test=FALSE
		# ),
		# list(
		# 	obj="mr_meta_fixed",
		# 	name="Fixed effects meta analysis (delta method)",
		# 	PubmedID="",
		# 	Description="",
		# 	use_by_default=FALSE,
		# 	heterogeneity_test=TRUE
		# ),
		# list(
		# 	obj="mr_meta_random",
		# 	name="Random effects meta analysis (delta method)",
		# 	PubmedID="",
		# 	Description="",
		# 	use_by_default=FALSE,
		# 	heterogeneity_test=TRUE
		# ),
		list(
			obj="mr_two_sample_ml",
			name="Maximum likelihood",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=TRUE
		),
		list(
			obj="mr_egger_regression",
			name="MR Egger",
			PubmedID="26050253",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=TRUE
		),
		list(
			obj="mr_egger_regression_bootstrap",
			name="MR Egger (bootstrap)",
			PubmedID="26050253",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_simple_median",
			name="Simple median",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_weighted_median",
			name="Weighted median",
			PubmedID="",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_penalised_weighted_median",
			name="Penalised weighted median",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_ivw",
			name="Inverse variance weighted",
			PubmedID="",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=TRUE
		),
		list(
			obj = "mr_ivw_radial",
			name = "IVW radial",
			PubmedID = "",
			Description = "",
			use_by_default = FALSE,
			heterogeneity_test = TRUE
		),
		list(
			obj="mr_ivw_mre",
			name="Inverse variance weighted (multiplicative random effects)",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_ivw_fe",
			name="Inverse variance weighted (fixed effects)",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_simple_mode",
			name="Simple mode",
			PubmedID="",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_weighted_mode",
			name="Weighted mode",
			PubmedID="",
			Description="",
			use_by_default=TRUE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_weighted_mode_nome",
			name="Weighted mode (NOME)",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_simple_mode_nome",
			name="Simple mode (NOME)",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_raps",
			name="Robust adjusted profile score (RAPS)",
			PubmedID="",
			Description="",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_sign",
			name="Sign concordance test",
			PubmedID="",
			Description="Tests for concordance of signs between exposure and outcome",
			use_by_default=FALSE,
			heterogeneity_test=FALSE
		),
		list(
			obj="mr_uwr",
			name="Unweighted regression",
			PubmedID="",
			Description="Doesn't use any weights",
			use_by_default=FALSE,
			heterogeneity_test=TRUE
		)
	)
	a <- lapply(a, as.data.frame)
	a <- plyr::rbind.fill(a)
	a <- as.data.frame(lapply(a, as.character), stringsAsFactors=FALSE)
	a$heterogeneity_test <- as.logical(a$heterogeneity_test)
	a$use_by_default <- as.logical(a$use_by_default)
	return(a)
}


#' List of parameters for use with MR functions
#'
#' The default is `list(test_dist = "z", nboot = 1000, Cov = 0, penk = 20, phi = 1, alpha = 0.05, Qthresh = 0.05, over.dispersion = TRUE, loss.function = "huber")`.
#'
#' @export
default_parameters <- function()
{
	list(
		test_dist = "z",
		nboot = 1000,
		Cov = 0,
		penk = 20,
		phi = 1,
		alpha = 0.05,
		Qthresh = 0.05,
		over.dispersion = TRUE,
                loss.function = "huber",
                shrinkage = FALSE
	)
}


#' Perform 2 sample IV using Wald ratio.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{causal effect estimate}
#' \item{se}{standard error}
#' \item{pval}{p-value}
#' \item{nsnp}{1}
#' }
mr_wald_ratio <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(length(b_exp) > 1)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA))
	}
	b <- b_out / b_exp
	se <- se_out / abs(b_exp)
	# sqrt((segd^2/gp^2) + (gd^2/gp^4)*segp^2 - 2*(gd/gp^3)) #full delta method with cov set to 0
	pval <- stats::pnorm(abs(b) / se, lower.tail=FALSE) * 2
	return(list(b=b, se=se, pval=pval, nsnp=1))
}


#' Perform 2 sample IV using simple standard error
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{causal effect estimate}
#' \item{se}{standard error}
#' \item{pval}{p-value}
#' }
mr_meta_fixed_simple <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA))
	}
	b <- sum(b_exp*b_out / se_out^2) / sum(b_exp^2/se_out^2)
	se <- sqrt(1 / sum(b_exp^2/se_out^2))
	pval <- 2 * stats::pnorm(abs(b) / se, lower.tail=FALSE)
	return(list(b=b, se=se, pval=pval, nsnp=length(b_exp)))
}



#' Perform 2 sample IV using fixed effects meta analysis and delta method for standard errors
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{causal effect estimate}
#' \item{se}{standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_meta_fixed <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 1)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA, Q =NA, Q_df =NA, Q_pval =NA))
	}
	ratio <- b_out / b_exp
	ratio.se <- sqrt((se_out^2/b_exp^2) + (b_out^2/b_exp^4)*se_exp^2 - 2*(b_out/b_exp^3)*parameters$Cov)
	res <- meta::metagen(ratio, ratio.se)
	b <- res$TE.fixed
	se <- res$seTE.fixed
	pval <- res$pval.fixed
	Q_pval <- stats::pchisq(res$Q, res$df.Q, lower.tail=FALSE)
	return(list(b=b, se=se, pval=pval, nsnp=length(b_exp), Q = res$Q, Q_df = res$df.Q, Q_pval = Q_pval))
}



#' Perform 2 sample IV using random effects meta analysis and delta method for standard errors
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{causal effect estimate}
#' \item{se}{standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_meta_random <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA, Q =NA, Q_df =NA, Q_pval =NA))
	}
	ratio <- b_out / b_exp
	ratio.se <- sqrt((se_out^2/b_exp^2) + (b_out^2/b_exp^4)*se_exp^2 - 2*(b_out/b_exp^3)*parameters$Cov)
	res <- meta::metagen(ratio, ratio.se)
	b <- res$TE.random
	se <- res$seTE.random
	pval <- res$pval.random
	Q_pval <- stats::pchisq(res$Q, res$df.Q, lower.tail=FALSE)
	return(list(b=b, se=se, pval=pval, nsnp=length(b_exp), Q = res$Q, Q_df = res$df.Q, Q_pval = Q_pval))
}



#' Maximum likelihood MR method
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{causal effect estimate}
#' \item{se}{standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_two_sample_ml <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA, Q=NA, Q_df=NA, Q_pval=NA))
	}
	loglikelihood <- function(param) {
		return(1/2*sum((b_exp-param[1:length(b_exp)])^2/se_exp^2)+1/2*sum((b_out-param[length(b_exp)+1]*param[1:length(b_exp)])^2/se_out^2))
	}
	opt <- try(stats::optim(
		c(b_exp, sum(b_exp*b_out/se_out^2)/sum(b_exp^2/se_out^2)),
		loglikelihood,
		hessian=TRUE,
		control = list(maxit=25000)), silent=TRUE)
	if(inherits(opt, "try-error"))
	{
		message("mr_two_sample_ml failed to converge")
		return(list(b=NA, se=NA, pval=NA, nsnp=NA, Q=NA, Q_df=NA, Q_pval=NA))
	}

	b <- opt$par[length(b_exp)+1]
	se <- try(sqrt(solve(opt$hessian)[length(b_exp)+1,length(b_exp)+1]))
	if(inherits(se, "try-error"))
	{
		message("mr_two_sample_ml failed to converge")
		return(list(b=NA, se=NA, pval=NA, nsnp=NA, Q=NA, Q_df=NA, Q_pval=NA))
	}

	pval <- 2 * stats::pnorm(abs(b) / se, lower.tail=FALSE)

	Q <- 2 * opt$value
	Q_df <- length(b_exp) - 1
	Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)

	return(list(b=b, se=se, pval=pval, nsnp=length(b_exp), Q = Q, Q_df = Q_df, Q_pval = Q_pval))
}



#' Egger's regression for Mendelian randomization
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List of with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error of MR estimate}
#' \item{pval}{p-value of MR estimate}
#' \item{b_i}{Estimate of horizontal pleiotropy (intercept)}
#' \item{se_i}{Standard error of intercept}
#' \item{pval_i}{p-value of intercept}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' \item{mod}{Summary of regression}
#' \item{dat}{Original data used for MR Egger regression}
#' }
mr_egger_regression <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	stopifnot(length(b_exp) == length(b_out))
	stopifnot(length(se_exp) == length(se_out))
	stopifnot(length(b_exp) == length(se_out))

	nulllist <- list(
			b = NA,
			se = NA,
			pval = NA,
			nsnp = NA,
			b_i = NA,
			se_i = NA,
			pval_i = NA,
			Q = NA,
			Q_df = NA,
			Q_pval = NA,
			mod = NA,
			smod = NA,
			dat = NA
		)
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 3)
	{
		return(nulllist)
	}

	sign0 <- function(x)
	{
		x[x==0] <- 1
		return(sign(x))
	}

	to_flip <- sign0(b_exp) == -1
	b_out = b_out*sign0(b_exp)
	b_exp = abs(b_exp)
	dat <- data.frame(b_out=b_out, b_exp=b_exp, se_exp=se_exp, se_out=se_out, flipped=to_flip)
	mod <- stats::lm(b_out ~ b_exp, weights=1/se_out^2)
	smod <- summary(mod)
	if(nrow(stats::coefficients(smod)) > 1)
	{
		b <- stats::coefficients(smod)[2,1]
		se <- stats::coefficients(smod)[2,2] / min(1,smod$sigma)
		pval <- 2 * stats::pt(abs(b / se), length(b_exp) - 2, lower.tail = FALSE)
		b_i <- stats::coefficients(smod)[1,1]
		se_i <- stats::coefficients(smod)[1,2] / min(1,smod$sigma)
		pval_i <- 2 * stats::pt(abs(b_i / se_i), length(b_exp) - 2, lower.tail = FALSE)

		Q <- smod$sigma^2 * (length(b_exp) - 2)
		Q_df <- length(b_exp) - 2
		Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)
	} else {
		warning("Collinearities in MR Egger, try LD pruning the exposure variables.")
		return(nulllist)
	}
 	return(list(b = b, se = se, pval = pval, nsnp = length(b_exp), b_i = b_i, se_i = se_i, pval_i = pval_i, Q = Q, Q_df = Q_df, Q_pval = Q_pval, mod = smod, dat = dat))
}



linreg <- function(x, y, w=rep(x,1))
{
	xp <- w*x
	yp <- w*y
	t(xp) %*% yp / (t(xp)%*%xp)

	bhat <- stats::cov(x*w,y*w, use="pair") / stats::var(x*w, na.rm=TRUE)
	ahat <- mean(y, na.rm=TRUE) - mean(x, na.rm=TRUE) * bhat
	yhat <- ahat + bhat * x
	se <- sqrt(sum((yp - yhat)^2) / (sum(!is.na(yhat)) - 2) / t(x)%*%x )

	sum(w * (y-yhat)^2)
	se <- sqrt(sum(w*(y-yhat)^2) /  (sum(!is.na(yhat)) - 2) / (sum(w*x^2)))
	pval <- 2 * stats::pnorm(abs(bhat / se), lower.tail=FALSE)
	return(list(ahat=ahat,bhat=bhat,se=se, pval=pval))
}


#' Run bootstrap to generate standard errors for MR
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters. Specifically, the `nboot` parameter can be specified for the number of bootstrap replications. The default is `parameters=list(nboot=1000)`.
#'
#' @export
#' @return List of with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error of MR estimate}
#' \item{pval}{p-value of MR estimate}
#' \item{b_i}{Estimate of horizontal pleiotropy (intercept)}
#' \item{se_i}{Standard error of intercept}
#' \item{pval_i}{p-value of intercept}
#' \item{mod}{Summary of regression}
#' \item{dat}{Original data used for MR Egger regression}
#' }
mr_egger_regression_bootstrap <- function(b_exp, b_out, se_exp, se_out, parameters)
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 3)
	{
		return(list(
			b = NA,
			se = NA,
			pval = NA,
			nsnp = NA,
			b_i = NA,
			se_i = NA,
			pval_i = NA,
			mod = NA,
			smod = NA,
			dat = NA
		))
	}
	nboot <- parameters$nboot
	# Do bootstraps
	res <- array(0, c(nboot+1, 2))
	# pb <- txtProgressBar(min = 0, max = nboot, initial = 0, style=3)
	for (i in 1:nboot)
	{
		# setTxtProgressBar(pb, i)
		#sample from distributions of SNP betas
		xs <- stats::rnorm(length(b_exp),b_exp,se_exp)
		ys <- stats::rnorm(length(b_out),b_out,se_out)

		# Use absolute values for Egger reg
		ys <- ys*sign(xs)
		xs <- abs(xs)

		#weighted regression with given formula
		# r <- summary(lm(ys ~ xs, weights=1/se_out^2))
		r <- linreg(xs, ys, 1/se_out^2)

		#collect coefficient from given line.
		res[i, 1] <- r$ahat
		res[i, 2] <- r$bhat
		# res[i, 1] <- r$coefficients[1,1]
		# res[i, 2] <- r$coefficients[2,1]

	}
	cat("\n")

	return(list(b = mean(res[,2], na.rm=TRUE), se = stats::sd(res[,2], na.rm=TRUE), pval = sum(sign(mean(res[,2],na.rm=TRUE)) * res[,2] < 0)/nboot, nsnp = length(b_exp), b_i = mean(res[,1], na.rm=TRUE), se_i = stats::sd(res[,1], na.rm=TRUE), pval_i = sum(sign(mean(res[,1],na.rm=TRUE)) * res[,1] < 0)/nboot))
}


#' Weighted median method
#'
#' Perform MR using summary statistics. Bootstraps used to calculate standard error.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters The default is `default_parameters()`. Specify the number of bootstrap replications to calculate the SE with `nboot`. The default is `list(nboot=1000)`.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' }
mr_weighted_median <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 3)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	b_iv <- b_out / b_exp
	VBj <- ((se_out)^2)/(b_exp)^2 + (b_out^2)*((se_exp^2))/(b_exp)^4
	b <- weighted_median(b_iv, 1 / VBj)
	se <- weighted_median_bootstrap(b_exp, b_out, se_exp, se_out, 1 / VBj, parameters$nboot)
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	return(list(b=b, se=se, pval=pval, Q=NA, Q_df=NA, Q_pval=NA, nsnp=length(b_exp)))
}


#' Simple median method
#'
#' Perform MR using summary statistics. Bootstraps used to calculate standard error.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters The number of bootstrap replications used to calculate the SE can be set through `parameters=list(nboot = 1000)`. The default is `list(nboot=1000)`.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{nsnp}{The number of SNPs}
#' }
mr_simple_median <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 3)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	b_iv <- b_out / b_exp
	b <- weighted_median(b_iv, rep(1/length(b_exp), length(b_exp)))
	se <- weighted_median_bootstrap(b_exp, b_out, se_exp, se_out, rep(1/length(b_exp), length(b_exp)), parameters$nboot)
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	return(list(b=b, se=se, pval=pval, nsnp=length(b_exp)))
}



#' Weighted median method
#'
#' New method from Jack
#'
#' @param b_iv Wald ratios
#' @param weights Weights of each SNP
#'
#' @export
#' @return MR estimate
weighted_median <- function(b_iv, weights)
{
	betaIV.order <- b_iv[order(b_iv)]
	weights.order <- weights[order(b_iv)]
	weights.sum <- cumsum(weights.order)-0.5*weights.order
	weights.sum <- weights.sum/sum(weights.order)
	below <- max(which(weights.sum<0.5))
	b = betaIV.order[below] + (betaIV.order[below+1]-betaIV.order[below])*
	(0.5-weights.sum[below])/(weights.sum[below+1]-weights.sum[below])
	return(b)
}

weighted_median <- function(b_iv, weights)
{
	betaIV.order <- b_iv[order(b_iv)]
	weights.order <- weights[order(b_iv)]
	weights.sum <- cumsum(weights.order)-0.5*weights.order
	weights.sum <- weights.sum/sum(weights.order)
	below <- max(which(weights.sum<0.5))
	b = betaIV.order[below] + (betaIV.order[below+1]-betaIV.order[below])*
	(0.5-weights.sum[below])/(weights.sum[below+1]-weights.sum[below])
	return(b)
}





#' Calculate standard errors for weighted median method using bootstrap
#'
#' Based on new script for weighted median confidence interval, update 31 July 2015.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param weights Weights to apply to each SNP.
#' @param nboot Number of bootstrap replications. The default is `1000`.
#'
#' @export
#' @return Empirical standard error
weighted_median_bootstrap <- function(b_exp, b_out, se_exp, se_out, weights, nboot)
{
	med <- rep(0, nboot)
	for(i in 1:nboot){
		b_exp.boot = stats::rnorm(length(b_exp), mean=b_exp, sd=se_exp)
		b_out.boot = stats::rnorm(length(b_out), mean=b_out, sd=se_out)
		betaIV.boot = b_out.boot/b_exp.boot
		med[i] = weighted_median(betaIV.boot, weights)
	}
	return(stats::sd(med))
}



#' Penalised weighted median MR
#'
#' Modification to standard weighted median MR
#' Updated based on Burgess 2016 "Robust instrumental variable methods using multiple candidate instruments with application to Mendelian randomization"
#'
#' @param b_exp Vector of genetic effects on exposure
#' @param b_out Vector of genetic effects on outcome
#' @param se_exp Standard errors of genetic effects on exposure
#' @param se_out Standard errors of genetic effects on outcome
#' @param parameters List containing `penk` - Constant term in penalisation, and `nboot` - number of bootstrap replications to calculate SE. `default_parameters()` sets `parameters=list(penk=20, nboot=1000)`.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' }
mr_penalised_weighted_median <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 3)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))
	betaIV <- b_out/b_exp # ratio estimates
	betaIVW <- sum(b_out*b_exp*se_out^-2)/sum(b_exp^2*se_out^-2) # IVW estimate
	VBj <- ((se_out)^2)/(b_exp)^2 + (b_out^2)*((se_exp^2))/(b_exp)^4
	weights <- 1/VBj
	bwm <- mr_weighted_median(b_exp, b_out, se_exp, se_out, parameters)
	penalty <- stats::pchisq(weights*(betaIV-bwm$b)^2, df=1, lower.tail=FALSE)
	pen.weights <- weights*pmin(1, penalty*parameters$penk) # penalized weights
	b <- weighted_median(betaIV, pen.weights) # penalized weighted median estimate
	se <- weighted_median_bootstrap(b_exp, b_out, se_exp, se_out, pen.weights, parameters$nboot)
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	return(list(b = b, se = se, pval=pval, nsnp=length(b_exp)))
}



#' MR median estimators
#'
#' @param dat Output from [harmonise_data()].
#' @param parameters List of parameters. The default is `default_parameters()`.
#'
#' @export
#' @return data frame
mr_median <- function(dat, parameters=default_parameters())
{
	if("mr_keep" %in% names(dat)) dat <- subset(dat, mr_keep)

	if(nrow(dat) < 3)
        {
		warning("Need at least 3 SNPs")
		return(NULL)
	}

	b_exp <- dat$beta.exposure
	b_out <- dat$beta.outcome
	se_exp <- dat$se.exposure
	se_out <- dat$se.outcome

	sm <- mr_simple_median(b_exp, b_out, se_exp, se_out, parameters)
	wm <- mr_weighted_median(b_exp, b_out, se_exp, se_out, parameters)
	pm <- mr_penalised_weighted_median(b_exp, b_out, se_exp, se_out, parameters)

	res <- data.frame(
		id.exposure = dat$id.exposure[1],
		id.outcome = dat$id.outcome[1],
		method = c("Simple median", "Weighted median", "Penalised median"),
		nsnp = length(b_exp),
		b = c(sm$b, wm$b, pm$b),
		se = c(sm$se, wm$se, pm$se),
		stringsAsFactors=FALSE
	)
	res$ci_low <- res$b - stats::qnorm(1-parameters$alpha/2) * res$se
	res$ci_upp <- res$b + stats::qnorm(1-parameters$alpha/2) * res$se
	res$pval <- c(sm$pval, wm$pval, pm$pval)
	return(res)
}


#' Inverse variance weighted regression
#'
#' The default multiplicative random effects IVW estimate.
#' The standard error is corrected for under dispersion
#' Use the [mr_ivw_mre()] function for estimates that don't correct for under dispersion.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_ivw <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	ivw.res <- summary(stats::lm(b_out ~ -1 + b_exp, weights = 1/se_out^2))
	b <- ivw.res$coef["b_exp","Estimate"]
	se <- ivw.res$coef["b_exp","Std. Error"]/min(1,ivw.res$sigma) #sigma is the residual standard error
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	Q_df <- length(b_exp) - 1
	Q <- ivw.res$sigma^2 * Q_df
	Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)
	# from formula phi =  Q/DF rearranged to to Q = phi*DF, where phi is sigma^2
	# Q.ivw<-sum((1/(se_out/b_exp)^2)*(b_out/b_exp-ivw.reg.beta)^2)
	return(list(b = b, se = se, pval = pval, nsnp=length(b_exp), Q = Q, Q_df = Q_df, Q_pval = Q_pval))
}

#' Unweighted regression
#'
#' The default multiplicative random effects IVW estimate.
#' The standard error is corrected for under dispersion
#' Use the [mr_ivw_mre()] function for estimates that don't correct for under dispersion.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters. The default is `default_parameters()`.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_uwr <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	ivw.res <- summary(stats::lm(b_out ~ -1 + b_exp))
	b <- ivw.res$coef["b_exp","Estimate"]
	se <- ivw.res$coef["b_exp","Std. Error"]/min(1,ivw.res$sigma) #sigma is the residual standard error
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	Q_df <- length(b_exp) - 1
	Q <- ivw.res$sigma^2 * Q_df
	Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)
	# from formula phi =  Q/DF rearranged to to Q = phi*DF, where phi is sigma^2
	# Q.ivw<-sum((1/(se_out/b_exp)^2)*(b_out/b_exp-ivw.reg.beta)^2)
	return(list(b = b, se = se, pval = pval, nsnp=length(b_exp), Q = Q, Q_df = Q_df, Q_pval = Q_pval))
}


#' Inverse variance weighted regression (multiplicative random effects model)
#'
#' Same as [mr_ivw()] but no correction for under dispersion.
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_ivw_mre <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	ivw.res <- summary(stats::lm(b_out ~ -1 + b_exp, weights = 1/se_out^2))
	b <- ivw.res$coef["b_exp","Estimate"]
	se <- ivw.res$coef["b_exp","Std. Error"]
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	Q_df <- length(b_exp) - 1
	Q <- ivw.res$sigma^2 * Q_df
	Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)
	# from formula phi =  Q/DF rearranged to to Q = phi*DF, where phi is sigma^2
	# Q.ivw<-sum((1/(se_out/b_exp)^2)*(b_out/b_exp-ivw.reg.beta)^2)
	return(list(b = b, se = se, pval = pval, nsnp=length(b_exp), Q = Q, Q_df = Q_df, Q_pval = Q_pval))
}


#' Inverse variance weighted regression (fixed effects)
#'
#' @param b_exp Vector of genetic effects on exposure.
#' @param b_out Vector of genetic effects on outcome.
#' @param se_exp Standard errors of genetic effects on exposure.
#' @param se_out Standard errors of genetic effects on outcome.
#' @param parameters List of parameters.
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{Q, Q_df, Q_pval}{Heterogeneity stats}
#' }
mr_ivw_fe <- function(b_exp, b_out, se_exp, se_out, parameters=default_parameters())
{
	if(sum(!is.na(b_exp) & !is.na(b_out) & !is.na(se_exp) & !is.na(se_out)) < 2)
	return(list(b=NA, se=NA, pval=NA, nsnp=NA))

	ivw.res <- summary(stats::lm(b_out ~ -1 + b_exp, weights = 1/se_out^2))
	b <- ivw.res$coef["b_exp","Estimate"]
	se <- ivw.res$coef["b_exp","Std. Error"]/ivw.res$sigma
	pval <- 2 * stats::pnorm(abs(b/se), lower.tail=FALSE)
	Q_df <- length(b_exp) - 1
	Q <- ivw.res$sigma^2 * Q_df
	Q_pval <- stats::pchisq(Q, Q_df, lower.tail=FALSE)
	# from formula phi =  Q/DF rearranged to to Q = phi*DF, where phi is sigma^2
	# Q.ivw<-sum((1/(se_out/b_exp)^2)*(b_out/b_exp-ivw.reg.beta)^2)
	return(list(b = b, se = se, pval = pval, nsnp=length(b_exp), Q = Q, Q_df = Q_df, Q_pval = Q_pval))
}

#' Robust adjusted profile score
#'
#' @inheritParams mr_ivw
#' @param parameters A list of parameters. Specifically, `over.dispersion` and `loss.function`.
#' `over.dispersion` is a logical concerning should the model consider overdispersion (systematic pleiotropy).
#' And `loss.function` allows using either the squared error loss (`"l2"`) or robust loss functions/scores (`"huber"` or `"tukey"`).
#' The default is `parameters=list(overdispersion = TRUE, loss.function = "tukey")`.
#'
#' @details This function calls the \code{mr.raps} package. Please refer to the documentation of that package for more detail.
#'
#' @references Qingyuan Zhao, Jingshu Wang, Jack Bowden, Dylan S. Small. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Forthcoming.
#'
#' @return List with the following elements:
#' \describe{
#' \item{b}{MR estimate}
#' \item{se}{Standard error}
#' \item{pval}{p-value}
#' \item{nsnp}{Number of SNPs}
#' }
#'
#' @export
mr_raps <- function(b_exp, b_out, se_exp, se_out, parameters = default_parameters()) {

    data <- data.frame(beta.exposure = b_exp,
                       beta.outcome = b_out,
                       se.exposure = se_exp,
                       se.outcome = se_out)
    out <- suppressMessages(
        mr.raps::mr.raps(data,
                         diagnostics = FALSE,
                         over.dispersion = parameters$over.dispersion,
                         loss.function = parameters$loss.function,
                         shrinkage = parameters$shrinkage))
    list(b = out$beta.hat,
         se = out$beta.se,
         pval = stats::pnorm(- abs(out$beta.hat / out$beta.se)) * 2,
         nsnp = length(b_exp))

}

#' MR sign test
#'
#' Tests how often the SNP-exposure and SNP-outcome signs are concordant.
#' This is to avoid the problem of averaging over all SNPs, which can suffer bias due to outliers with strong effects; and to avoid excluding SNPs which is implicit in median and mode based estimators.
#' The effect estimate here is not to be interpreted as the effect size - it is the proportion of SNP-exposure and SNP-outcome effects that have concordant signs.
#' e.g. +1 means all have the same sign, -1 means all have opposite signs, and 0 means that there is an equal number of concordant and discordant signs.
#' Restricted to only work if there are 6 or more valid SNPs.
#'
#' @param b_exp Vector of genetic effects on exposure
#' @param b_out Vector of genetic effects on outcome
#' @param se_exp Not required
#' @param se_out Not required
#' @param parameters Not required
#'
#' @export
#' @return List with the following elements:
#' \describe{
#' \item{b}{Concordance (see description)}
#' \item{se}{NA}
#' \item{pval}{p-value}
#' \item{nsnp}{Number of SNPs (excludes NAs and effect estimates that are 0)}
#' }
mr_sign <- function(b_exp, b_out, se_exp=NULL, se_out=NULL, parameters=NULL)
{
	b_exp[b_exp == 0] <- NA
	b_out[b_out == 0] <- NA
	if(sum(!is.na(b_exp) & !is.na(b_out)) < 6)
	{
		return(list(b=NA, se=NA, pval=NA, nsnp=NA))
	}
	x <- sum(sign(b_exp) == sign(b_out), na.rm=TRUE)
	n <- sum(!is.na(b_exp) & !is.na(b_out))

	out <- stats::binom.test(x=x, n=n, p=0.5)
	b <- (out$estimate - 0.5) * 2
	names(b) <- NULL
	pval <- out$p.value
	return(list(b=b, se=NA, pval=pval, nsnp=n))
}
